Cell Biology

Faculty and Research Interests

Bernard W. Spur, PhD

Associate Professor
Science Center 102a
856-566-7016
spurbw@umdnj.edu

Education

University Dusseldorf, West Germany,
PhD (Chemistry)

Research Interests

Our research focuses on lipid mediators of inflammation (leukotrienes, prostaglandins, isoprostanes, neuroprostanes and their metabolites) and lipid mediators of resolution (lipoxin, aspirin-triggered 15(R)-lipoxin, resolvins, neuroprotectins and their metabolites). We developed new and general stereoselective syntheses of these lipid mediators in both naturally occurring as well as in isotopic labeled form. We reported the first general syntheses of isoprostanes and phytoprostanes via a two-component coupling process combined with diastereoselective protonation under reagent control. This is the shortest and most flexible synthesis reported to date. We further reported the first total syntheses of resolvin D2 and D5 shortly after their discovery. (Serhan et al. J Exp Med. 2002) (Rodriguez and Spur; Tetrahedron Lett. 2004, Tetrahedron Lett. 2005)

In earlier work we investigated the biological activities of lipoxin and their analogs on human neutrophils and eosinophils. Lipoxin A4 showed a profound anti-inflammatory activity by inhibiting the action of pro-inflammatory lipid mediators and blocked the chemotactic activity of all known chemotactic active agents.

We had previously monitored lipoxin in humans with various diseases at London University. This work was done in collaboration with the Harvard Medical School and University of Pennsylvania/Scripps Institute. In samples from healthy patients we observed a correlation between high levels of lipoxin and low levels of pro-inflammatory leukotrienes. In contrast, patients with chronic diseases had low levels of lipoxin but high levels of leukotrienes and isoprostanes.

In a subsequent human trial (Christie, Spur, Lee; Amer. Rev. Respir. Dis. 1990) we were able to show that lipoxin A4 was safe and blocked airway challenge and hyperreactivity in asthmatic patients. This trial established for the first time the important protective role of lipoxin in asthma.

Acute inflammation has several outcomes that include resolution, or if not controlled, progression to chronic inflammation. Resolution had been considered a passive process in vivo, but with identification of the endogenous anti-inflammatory and pro-resolving lipid mediator lipoxin A4 it became clear that resolution in humans is an active process involving biosynthesis of these lipid mediators at the side of inflammation. In the case that the biosynthesis is compromised or these pro-resolution mediators are not formed we observe chronic inflammatory diseases.

Oxidative stress, as measured by increased urinary isoprostane excretion, is a biochemical marker of inflammation that can be down regulated by lipoxins and resolvins. We described high levels of isoprostanes in patients with Alzheimer’s disease. T.P. Stein found similar results in children with Autism. In addition, we measured low contents of docosahexaenoic acid, the major essential fatty acid in brain in patients with Alzheimer’s disease. In the clinical situation, fatty acid deficiencies can be reversed by supplying this fatty acid to the patient with improvements in symptoms; however in Alzheimer’s patients the biosynthesis of the anti-inflammatory resolvins has been reported to be >95% reduced compared to age matched healthy individuals, explaining the marginal benefit in clinical trials with fish oil supplementation.

Earlier we described the effects of dietary enrichment with eicosapentaenoic and docosahexaenoic acid on in vitro neutrophil and monocyte leukotriene generation and neutrophil function. These studies were performed in healthy individuals as well as in patients with rheumatoid arthritis and mild to moderate asthma. Overall we saw clinically relevant improvement using fish oil in certain patients but not in all. Today we can address this by an impaired biosynthesis of the pro-resolution mediators lipoxin and resolvins, a finding now under investigation in autism. Our current studies in autism include analysis of polymorphic variants of genes of docosahexaenoic acid (DHA) synthesis and metabolism to predict responses to DHA therapy as assessed by behavioral and functional improvement. Other genes related to detoxification pathways in the brain are included. The gene analysis will be performed using SNPstream (AGRE 500K chip for SNPs and HapMap SNPs) (by W.G. Johnson and S. Stenross, UMDNJ-RWJMS Department of Neurology, Piscataway). These studies will help us to pinpoint defects in biosynthesis of pro-resolution mediators. We are investigating the effects of low dose docosahexaenoic acid on children with autism by analyzing the change in the biomarkers of oxidative stress (isoprostanes) and pro-resolution mediators. High dose docosahexaenoic acid can have negative impact by inhibiting the biosynthesis of the resolvins and providing the substrate for auto-oxidation to neuroprostanes. We observed clinical improvements in 7 out of 42 patients with a low dose docosahexaenoic acid intervention. (X. Ming, New Jersey Medical School UMDNJ-Newark) Subsequent studies will address the imbalance of resolution in other chronic inflammatory diseases.

At present we have started to proceed with the development of lipoxin and several resolvins as drug candidates according to the guidelines of the FDA. Meetings with the FDA and the NIH indicated a great interest in these natural anti-inflammatory compounds. As part of this effort we are developing new methods for the large-scale synthesis of these mediators including asymmetric reduction and carbon-carbon formation in water.

Recent Publications

1. Danielsson K. G., Swahn M. L., Marions L., Wong P. Y. K., Rodriguez A., Spur B. W., Bygdeman M. Comparison between oral and vaginal administration of misoprostol on uterine contractility. Obstet. Gynecol. 1999, 93(2), 275-280.
2. Rodríguez A., Nomen M., Spur B. W., Godfroid J. -J. Synthesis of 2H3-labelled misoprostol and its primary plasma metabolite. J. Labelled Cpd. Radiopharm. 1999, 42, 843-850.
3. Ho H. M. C., Tseng S. L., Lin L. H., Chen K. T., Chiang H. S., Spur B. W., Wong P. Y. K, Sheu M. T. The percutaneous penetration of prostaglandin E1 and its alkyl esters. J. Control. Release 1999, 58(3), 349-355.
4. Rodríguez A., Nomen M., Spur B. W., Godfroid J. -J. Selective oxidation of primary silyl ethers and its application to the synthesis of natural products. Tetrahedron Lett. 1999, 40, 5161-5164.
5. Rodríguez A., Nomen M., Spur B. W., Godfroid J. -J. An efficient asymmetric synthesis of prostaglandin E1. Eur. J. Org. Chem. 1999, 2655-2662.
6. Rodríguez A., Nomen M., Spur B. W., Godfroid J. -J., Lee T. H. Total synthesis of lipoxin A4 and lipoxin B4 from butadiene. Tetrahedron Lett. 2000, 41, 823-826.
7. Rodríguez A., Nomen M., Spur B. W., Godfroid J. -J., Lee T. H. Total synthesis of leukotrienes from butadiene. Eur. J. Org. Chem. 2000, 2991-3000.
8. Rodríguez A., Nomen M., Spur B. W., Godfroid J. -J., Lee T. H. Total synthesis of 12(R)-HETE, 12(S)-HETE, 2H2 -12(R)-HETE and LTB4 from racemic glycidol via hydrolytic kinetic resolution. Tetrahedron 2001, 57, 25-37.
9. Tuppo E. E., Forman L. J., Spur B. W., Chan-Ting R. E., Chopra A., Cavalieri T. A. Signs of Lipid Peroxidative Damage as Measured in the Urine of Patients with Alzheimer=s Disease. Brain Res. Bull. 2001, 54(5), 565-568.
10. Rodriguez A. R., Spur B. W. Total synthesis of aspirin-triggered 15-epi-lipoxin A4. Tetrahedron Lett. 2001, 42, 6057-6060.
11. Spokas E.G.,   Spur B. W.. Rapid Measurement of Low levels of Sodium, Potassium-ATPase Activity by Ascorbic Acid Reduction without Strong Acid. Analytical Biochemistry 2001, 299, 112-116.
12. Rodriguez A.R., Spur B. W. Total synthesis of isoprostanes via the two-component coupling process. Tetrahedron Lett. 2002, 43, 4575-4579.
13. Rodriguez A.R., Spur B. W. Total synthesis of E1 and E2 isoprostanes by diastereoselective protonation. Tetrahedron Lett. 2002, 43, 9249-9253.
14. Rodriguez A.R., Spur B. W. First total synthesis of the E type I phytoprostanes. Tetrahedron Lett. 2003, 44, 7411-7415.
15. Rodriguez A.R., Spur B. W. First total synthesis of  7(S), 16(R), 17(S)-Resolvin D2, a potent anti-inflammatory lipid mediator. Tetrahedron Lett. 2004, 45, 8717-8720.
16. Rodriguez A.R., Spur B. W. First total synthesis of  7(S), 17(S)-Resolvin D5, a potent anti-inflammatory docosanoid. Tetrahedron Lett. 2005, 46, 3623-3627.
17. Spokas E.G., Spur B.W., Smith H., Kemp F.W., Bodgen J.D. Tissue Lead Concentration during Chronic Exposure of Pimephales promelas (Fathead Minnow) to Lead Nitrate in Aquarium Water. Environ. Sci. Technol. 2006, 40, 6852-6858.
18. Spokas E.G., Harshman S., Cohen G.M., Jiang C., Levine J.M., Rodriguez A.R., Foglein J., Spur B.W. Release of the Lipid Marker 8-epi-PGF2α from Isolated Gill Pavement Cells. Environ. Toxicol. Chem. 2008, 27 1569-1575.
19. Stein T.P., Scholl T.O., Schluter M.D., Leskiw M.J., Spur B.W., Rodriguez A.R., Chen X. H. Oxidative Stress early in Pregnancy and Pregnancy outcome. In press 2008

(further bibliography)